Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
  • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
  • C07D501/36—Methylene radicals, substituted by sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• This invention relates to a compound of the formula: [wherein m is an integer of 0 or 1; n is an integer of 2 to 5, inclusive] or a pharmaceutically acceptable salt thereof, particularly an acid addition salt and to a process for producing the same. It also relates to a pharmaceutical composition and an antibiotic use thereof.
• the present inventors have found through investigation of a series of ester derivatives of compound (II), that the compound of formula (I) or an acid addition salt thereof can be absorbed well through the gastrointestinal tract until the unesterified form of compound (I) is liberated soon after the absorption and is well transferred into the circulation to produce a high blood level of compound (II) . They have also found that the compound (I) is effective as an orally administrable broad- spectrum antibiotic having activity not only against gram-positive and gram-negative bacteria but also active against resistant strains thereof. It is also found that conversion of this compound (I) to an acid addition salt increases the water solubility of the ester to thereby improve its rate of absorption, stabilizes compound (I) and facilitates both.the isolation of compound (I) and the pharmaceutical processing thereof.
• cephalosporin compound (I) the group represented by the formula: [wherein m and n are as defined hereinbefore] at the carboxy ester moiety in 4-position of the cephalosporin nucleus is a cycloalkyl group containing 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. or a cycloalkylmethyl group of 4 to 7 carbon atoms such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.
• Preferred species are cyclopentyl, cyclohexyl, cyclopentylmethyl and cyclohexylmethyl, with cyclopentylmethyl and cyclohexylmethyl being the most preferred.
• compound (I) Since compound (I) is basic in itself, it can be converted to acid addition salts. Generally, one molar equivalent of compound (I) forms an acid addition salt with 1 or 2 molar equivalents of an acid.
• Preferred examples of the acid that can be used for the formation of such acid addition salt include acids which are generally known to provide pharmaceutically acceptable salts in the field of penicillins and cephalosporins.
• such inorganic acids as hydrochloric acid, sulfuric acid, phosphoric acid, etc.
• organic acids as maleic acid, acetic acid, citric acid, succinic acid, tartaric acid, malic acid, malonic acid, fumaric acid, benzoic acid, mandelic acid, ascorbic acid, methanesulfonic acid, etc. may be mentioned.
• the acid addition salt of compound (I) is preferably the monohydrochloride or dihydrochloride, and preferably the dihydrochloride.
• the aminothiazole group of compound (I) or acid addition salt thereof may exist as an iminothiazoline group which is a tautomer thereof. Since the compound (I) or acid addition salt thereof contains an asymmetric carbon atom in the 4-carboxy ester moiety of the cephalosporin nucleus, it may exist as two optical isomers (D- and L-isomers). Therefore, the compound (I) or acid addition salt thereof may be used optionally in the form of a racemic compound, either the D-isomer or the L-isomer, or a mixture of optional proportions of such isomers.
• the compound (I) and acid addition salt thereof are absorbed well from the gastrointestinal tract and, upon absorption, its 4-carboxy ester moiety is rapidly hydrolyzed by the enzymes in the body to give the non-ester form of compound (I), that is compound (II).
• the compound (II) is highly active against gram-positive bacteria such as Staphylococcus aureus, etc. and gram-negative bacteria such as Escherichia coli, Klebsiella.pneumoniae, Proteus vulgaris, Proteus mirabilis and Proteus morganii.
• the compound (I) When administered by the oral route, the compound (I) yields a high concentration in blood and it is effective for the treatment of infections in human and other manmalia caused by said bacteria, for example respiratory or urinary infections.
• the compound (I) or an acid addition salt thereof according to the present invention is low in toxicity (LD 50 ⁇ 3 g/kg, mice, oral) and can orally be administered, and can be formulated into capsules, powders, fine granules, granules or tablets, etc., in admixture with the common pharmaceutically acceptable excipients e.g. starch, lactose, calcium carbonate, calcium phosphate, etc., binders e.g. starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc., lubricants e.g. magnesium stearate, talc, etc., or/and disintegrators e.g.
• the common pharmaceutically acceptable excipients e.g. starch, lactose, calcium carbonate, calcium phosphate, etc.
• binders e.g. starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.
• Granules can also be produced by blending the compound (I) or acid addition salt thereof with about 1 to 5 molar equivalents of a solid organic acid, e.g. citric acid, malic acid, tartaric acid, succinic acid, ascorbic acid, mandelic acid, etc. Such granules can be further processed into capsules, tablets, etc. by the established pharmaceutical procedure.
• a solid organic acid e.g. citric acid, malic acid, tartaric acid, succinic acid, ascorbic acid, mandelic acid, etc.
• the recommended dosage of compound (I) or acid addition salt thereof is 0.3 to 5 grams and preferably 0.5 to 3 grams per day per adult human, given in 3 to 4 divided doses.
• the compound (I) or acid addition salt thereof can be produced by known methods per se i.e. the processes described in U .S. Patents 4080498 and 4189479 and Japanese Published Unexamined Patent Application No. 77690/82, for instance.
• the compound (I) or a salt thereof can also be produced by esterifying compound (II) or a salt thereof with a compound of the formula: [wherein X is a halogen atom; m and n are as defined hereinbefore].
• the halogen X may for example be chlorine, bromine or iodine.
• the starting compound (II) for the present invention can be used in the contemplated reaction after converting it to its acid addition salt with an inorganic acid, e.g. hydrochloric acid, sulfuric acid, nitric acid, etc. or an organic acid, e.g. oxalic acid, p-toluenesulfonic acid, etc. or its salt with a base such as alkali metals, e.g. sodium, potassium, etc., alkaline earth metals, e.g. calcium, magnesium, etc. or an organic amine, e.g. triethylamine, trimethylamine, pyridine, collidine, lutidine, etc.
• an inorganic acid e.g. hydrochloric acid, sulfuric acid, nitric acid, etc. or an organic acid, e.g. oxalic acid, p-toluenesulfonic acid, etc. or its salt with a base such as alkali metals, e.
• the starting compound (III) is used in a proportion of about 1 to 10 molar equivalents, preferably 1 to 1.5 molar equivalen to compound (II) or a salt thereof.
• This esterification reaction is generally conducted in a solvent inert to the reaction.
• amides such as N,N-dimethylformamide (hereinafter referred to as DMF), N,N-dimethylacetamide (hereinafter referred to as DMAC), hexamethylphosphorotriamide (hereinafter referred to as HMPA) etc., halogenated hydrocarbons such as dichloromethane, chloroform, etc., sulfoxides such as dimethylsulfoxide (hereinafter referred to as DMSO), sulfolane, etc., ethers such as dioxane, tetrahydrofuran (hereinafter referred to as THF), etc., ketones such as acetone, methyl ethyl ketone etc., nitriles such as acetonitrile, etc., and anhydrous liquefied sulfur dioxide.
• DMF N,N-dimethylformamide
• DMAC N,N-dimethylacetamide
• HMPA hexamethylphosphorotriamide
• Preferred species among these solvents are DMF, DMAC, HMPA, acetone, acetonitrile, anhydrous liquefied sulfur dioxide.
• This esterification reaction is conducted generally at a temperature of -20 to 20°C.
• a catalyst is not always needed. It may, however, be conducted in the presence of a catalyst such as a phase transfer catalyst, e.g. 18-crown-6.
• the reaction is desirably conducted at a temperature near the boiling point of the solvent, i.e. -10 to -20°C. While the reaction time varies with different species of reactants and types of solvents, it is generally about 10 minutes to about 6 hours.
• the compound (I) or an acid addition salt thereof can also be produced by the following process, for instance.
• a compound of formula: [wherein A is an amino group or an acylamino group other than 2-(2-aminothiazol-4-yl)acetylamino] is reacted with a compound of formula (III) in the same manner as the above-mentioned esterification reaction.
• A is an acylamino group
• the resulting ester is further reacted with phosphorous pentachloride and, then, with an alcohol, e.g. methanol, ethanol, propanol, isopropyl alcohol, n-butanol, etc.
• an alcohol e.g. Journal of Medicinal Chemistry 18, 992 (1975), and German Laid-open Patent Applications (Offenlegungsschriften) Nos. 2460331 and 2460332
• the resulting compound which can be represented by the formula: [wherein the symbols have the same meanings as defined hereinbefore] is acylated with the compound of the formula: which is 2-(2-aminothiazol-4-y
• the acyl group may be any such group that is commonly used in the field of cephalosporin compounds.
• Preferred examples of the acylamino group include acetylamino, benzoylamino, phenylacetylamino, thienylacetylamino, phenyloxyacetyl- amino and 5-amino-5-carboxyvalerylamido.
• the amino group may optionally be protected with phthaloyl or the like. When A is an amino group or an amino-substituted acylamino group, these amino groups are preferably protected.
• Protective groups that can be used for this protection include, among others, t-butoxycarbonyl, carboxybenzyloxy, 2-hydroxy-1-naphthocarbonyl, trichloroethoxycarbonyl, 2-ethoxycarbonyl-1-methylvinyl and 2-methoxycarbonyl-1-methylvinyl.
• Deacylation of the ester compound produced by reacting compound (IV), wherein A is an acylamino group, with compound (III) is carried out in a per se known manner. Generally, about 2 to 5 molar equivalents of phosphorous pentachloride and about 10 to 40 molar equivalents of alcohol are used for each molar equivalent of the material ester compound.
• This reaction is generally conducted in an inert solvent such as halogenated hydrocarbons, e.g. dichloromethane, chloroform, etc.
• a tertiary amine such as triethylamine, pyridine, N,N-dimethylaniline, etc.
• the reaction is carried out within the temperature range of about -40 to 20°C. A reaction time of 1 hour is generally sufficient.
• compound (VI) In reacting the resulting compound (V) with compound (VI) to produce compound (I) or an acid addition salt thereof, the amino group of compound (VI) is preferably protected.
• Protective groups may be the same as those mentioned for the protection of the amino group of compound (IV).
• compound (VI) In conducting this acylation reaction, compound (VI) may be used in the form of a reactive derivative such as the corresponding acid halide, acid anhydride, mixed acid anhydride, active amide, activated ester, etc.
• the mixed acid anhydride mentioned above includes, for example, mixed acid anhydrides with carbonic acid monoesters such as carbonic acid monomethyl ester, carbonic acid monoisobutyl ester, etc. and mixed acid anhydrides with lower or 2 to 5 carbon atoms alkanoic acids which may optionally be substituted by halogen, such as pivalic acid, trichloroacetic acid, etc.
• a suitable condensing agent When compound (VI) is used is the form of a free compound or a salt, a suitable condensing agent is employed.
• suitable condensing agent include dehydrating agents such as N,N'-disubstituted carbodiimides, e.g. N,N'-dicyclohexylcarbodiimide, etc., azolides, e.g. N,N'- carbonylimidazole, N,N'-thienyldiimidazole, etc., N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline, phosphorous oxychloride, alkoxyacetylene, e.g. ethoxyacetylene, etc., etc. It is considered that when such a condensing agent is employed, the reaction proceeds via formation of a reactive derivative at the carboxyl function.
• This reaction can generally be conducted in a solvent.
• a solvent there may be employed any of the common solvents, as well as a suitable mixture thereof, which does not interfere with the reaction, such as water, acetone, diisobutyl ketone, THF, ethyl acetate, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethylene, pyridine, dimethylaniline, DMF, DMAC, DMSO, etc.
• the reaction temperature is virtually optional but the reaction is generally conducted under cooling or at room temperature. When the reaction proceeds with liberation of acid, a base is added to the reaction system as required.
• the base mentioned above is exemplified by aliphatic, aromatic or heterocyclic-nitrogen bases, alkali metal carbonates and alkali metal hydrogen carbonates, such as triethylamine, N,N-dimethylaniline, N-ethylmorpholine, pyridine, collidine, 2.6-lutidine, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.
• alkali metal carbonates and alkali metal hydrogen carbonates such as triethylamine, N,N-dimethylaniline, N-ethylmorpholine, pyridine, collidine, 2.6-lutidine, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.
• water is preferably eliminated from the solvent.
• the reaction may be carried out under anhydrous conditions in an inert gas such as nitrogen gas.
• the reaction product has a protective group, the protective group is eliminated by a per se known procedure.
• Compound (I) or an acid addition salt thereof can also be produced by reacting compound (V) with a 4-halo-3-oxobutyryl halide, which can be obtained by reacting diketene with a halogen e.g. chlorine, bromine, iodine, in an equimolar ratio, to give a compound of formula (VII): [wherein m and n are as defined hereinbefore; Y is a halogen atom, e.g. chlorine, bromine, iodine] and reacting compound (VII) further with thiourea.
• a halogen atom e.g. chlorine, bromine, iodine
• reaction of compound (VII) with thiourea the latter may be used either as such or in such other forms as salts with alkali metals such as lithium, sodium, potassium, etc., ammonium salts, etc.
• the reaction is generally conducted by admixing and reacting the two reactants in an equimolar ratio in a solvent and, if necessary, in the presence of 1 to 2 molar equivalents of a base.
• the solvent suitable for this reaction includes water, methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, THF, ethyl acetate, DMF, DMAC, DMSO, etc.
• hydrophilic solvents can be used in admixture with water.
• the base mentioned above includes, among others, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkali metal carbonates such as sodium carbonate, potassium carbonate, etc., alkali metal hydrogen carbonates such as sodium hydrogen carbonate, and organic tertiary amines such as triethylamine, trimethylamine, pyridine, etc.
• the reaction temperature is preferably conducted under cooling. The reaction proceeds fast and generally goes to completion within 10 minutes, although a reaction time of as long as 30 minutes or more may be required in some cases.
• the compound (VII) can be easily produced by the above process or per se known procedures.
• This reaction (2) can be usually carried out in a solvent inert to the reaction.
• a solvent inert Any conventional solvent such as water, THF, ethyl acetate, dioxane, acetonitrile, chloroform, dichloromethane, DMF, DMAC, DMSO and a mixture thereof can be used.
• an inorganic base in the reaction system is preferable.
• the base are alkali metal carbonate e.g. sodium carbonate and potassium carbonate, alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, alkaline earth metal carbonate e.g. calcium carbonate and so on.
• Amount of the base present in the reaction is about 1 to 3 moles to a co-reactant of the compound (IX).
• the reaction temperature range is not particularly limited, but normally room temperature or about 15°C to 60°C, and the reaction time is roughly from 30 minutes to 3 hours, depending on kinds of solvents and temperature.
• the objective compound (I) or an acid addition salt thereof includes the ⁇ 2 -isomer
• the latter can be isomerized to the ⁇ 3 -isomer by a per se known procedure, for example the process described in Journal of Medicinal Chemistry 18, 986 (1975), or the entirety is first converted to the corresponding S-oxide and the resulting 6 3- isomer is then reduced to the desired compound (I) or a salt thereof.
• the objective compound (I) When the objective compound (I) is produced in a free form, it can be converted to a desired acid addition salt thereof by dissolving the compound (I) in a free form in an inert solvent such as dichloromethane, chloroform or the like and adding about 1 to 10 molar equivalents of an-acid.
• compound (I) or an acid addition salt thereof When compound (I) or an acid addition salt thereof is obtained as a racemic isomer, it can be resolved into optically active compounds (D-and L-isomers) by a per se known procedure.
• the resulting compound (I) or an acid addition salt thereof can be isolated and purified by a per se known procedures such as solvent extraction, pH adjustment, phase transfer, crystallization, recrystallization, chromatography, etc.
• the starting compound (III) can be produced by a procedure known per se. Moreover, compound (III) can also be produced by the procedures schematically illustrated below. In the above formulas, m and n are as defined hereinbefore.
• the compound wherein X is iodine i.e. an iodoethyl acylate
• the acid chloride (VIII) can be produced by reacting the acid chloride (VIII) with paral- dehyde or acetaldehyde in the presence of a Lewis acid and reacting the resulting chloroethyl acylate with sodium iodide.
• the first step reaction is conducted in the presence of a Lewis acid catalyst such as anhydrous zinc chloride, aluminum chloride, stannic chloride, etc.
• This reaction proceeds under cooling at about -40 to +30°C, preferably at about -40 to 0°C, or under heating at about 30 to 140°C, preferably at about 90 to 140°C. While the reaction time varies with the reaction temperature used, it is about 1 to 3 hours under cooling and about 1 to 6 hours under heating. The reaction proceeds satisfactorily even in the absence of a solvent.
• the reaction mixture is subjected to distillation, column chromatography or the like to recover the chloroethyl acylate.
• This chloroethyl acylate is then reacted with sodium iodide to give the iodoethyl acylate (the second step reaction).
• This second step reaction is conducted in the common solvent, e.g. acetone, acetonitrile, DMF, DMSO, etc.
• the reaction temperature may be as mild as room temperature to about 40 to 50°C.
• the reaction time is about 15 minutes to 6 hours, preferably about 15 minutes to 2 hours.
• the reaction product can be isolated and purified, for example,by solvent extraction, pH adjustment, distillation, distillation under reduced pressure, phase transfer, chromatography, etc.
• the aqueous layer is extracted with 200 ml of ethyl acetate and the organic layers are combined and washed 3 times with 300 ml portions of ice-water and once with 300 ml of saturated aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate.
• the solvent is distilled off under reduced pressure and isopropyl ether is added to the residue.
• the resulting powder is collected by filtration and recrystallized from acetone-isopropyl ether to give 3.9 g of the above-identified compound as colorless crystals.
• Step A Preparation of 1-(cyclohexanecarbonyl- oxy)ethyl 7 ⁇ -amino-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiojmethyl]ceph-3-em-4-carboxylate dihydrochloride:
• the reaction mixture is then poured into a mixture of 60 ml of dichloromethane and 60 ml of 0.1N HCl, and the aqueous layer is separated.
• the aqueous layer is adjusted to pH 6.0 with a saturated aqueous solution of sodium hydrogen-carbonate and extracted with dichloromethane.
• the organic layer is admixed with water and adjusted to pH 2.0 with 4N HCl.
• the aqueous layer is separated and dichloromethane is removed from the aqueous layer under reduced pressure.
• the aqueous layer is lyophilized to give 2.65 g of the titled compound.
• IR(Nujol) cm -1 1785, 1755, 1675
• Step B To a mixture of 30 ml of water and 30 ml of dichloromethane is added 1.73 g of the compound prepared in the above step A. While the mixture is stirred, 0.56 g of sodium hydrogencarbonate is added. The organic layer is separated and dried over anhydrous calcium chloride. After the calcium chloride is filtered off, a solution of 0.61 g of (2-aminothiazol-4-yl)acetic acid hydrochloride and 0.64 g of dicyclohexylcarbodiimide in 20 ml of dimethylformamide is added to the organic layer and the mixture is stirred at room temperature.
• the organic layer is washed successively with ice water (50 ml) and saturated aqueous solution of sodium chloride (50 ml) and dried over anhydrous magnesium sulfate. After removing of. magnesium sulfate by filtration, the filtrate is concentrated in vacuo. The residue is dissolved in acetone and insolubles are filtered off. To the filtrate is added isopropyl ether until powdery precipitates are deposited. The precipitates are obtained at white powdery product. The yield is 0.14 g.
• Compound No. 1 according to Example 1 (334.4 g; 250 g as the non-ester compound) is evenly admixed with 70.5 g of hydroxypropylcellulose and 70.5 g of carboxymethylcellulose. The resulting mixture is filled into capsules in amounts of 237.7 mg (125 mg as the non-ester) by the established pharmaceutical procedure.
• Compound No. 2 according to Example 2 (373.4 g; 250 g as the non-ester compound) is evenly admixed with 70 g of starch and 6 g of hydroxypropylcellulose. The mixture is pressed into tablets by the established pharmaceutical procedure to provide tablets each containing 224.7 mg (125 mg as the non-ester).
• the compounds produced according to the Examples (Compound Nos. 2, 4, 6 and 8) and, as a reference control, pivaloyloxymethyl ester of compound (II) (hereinafter referred to as Compound A) are orally administered to mice at a common dose level of 100 mg/kg (as the non-ester, i.e. compound (II) per mouse).
• the plasma concentrations of compound (II) at 0.25, 0.5, 1.0 and 2.0 hours are determined by the cup assay method (using Proteus mirabilis Eb 313 as the test organism) and the area under plasma concentration- time curve (AUC) over 0 to 2 hours is calculated.

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• 1982
  • 1982-11-15 JP JP57200898A patent/JPS5989691A/ja active Granted
• 1983
  • 1983-11-10 GR GR72939A patent/GR79385B/el unknown
  • 1983-11-11 EP EP83306923A patent/EP0109294A3/de not_active Ceased
  • 1983-11-14 ES ES527244A patent/ES8505375A1/es not_active Expired
  • 1983-11-14 CA CA000441084A patent/CA1207319A/en not_active Expired
  • 1983-11-14 PT PT77664A patent/PT77664B/pt unknown
  • 1983-11-15 KR KR1019830005415A patent/KR840006810A/ko not_active Abandoned
• 1984
  • 1984-07-02 ES ES533934A patent/ES533934A0/es active Granted
• 1985
  • 1985-04-01 ES ES541823A patent/ES541823A0/es active Granted

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